Squamous cell carcinoma of the head and neck (HNSCC) is the sixth most common cancer in the developed world, and is likely associated with chemical carcinogens present in tobacco, and, less clearly, with oncogenic viruses. In spite of its frequency, little is known about the molecular events which contribute to disease initiation and progression. Deletion or mutation of p53 characterizes benign and malignant neoplasms from a broad spectrum of tissues types, including oral mucosa. Although several studies have demonstrated p53 aberrations in HNSCC, the functional contribution of such mutations to tumor development in this system remains unproven. Our studies, therefore, have focussed on determining the likely role of HNSCC-derived p53 mutants on tumor establishment and progression, using in vivo assays of p53 function.